Alkamine esters of para amino benzoic acid



Patented Jan. 18, 1949 ALKAMINE ESTERTS 0F PARA AMINO BENZOIC ACID Arthur C. Cope, Englewood, N. J. assignor to Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No Drawing. Application October 5, 1943,

Serial No. 505,041

4 Claims. (Cl. 260-472) This invention relates to new esters of p-amino benzoic acid which have valuable properties for use as local anesthetics. In general, the new compounds combine high effectiveness with relatively low toxicity and are relatively non-irritating. These new anesthetics may be used by infiltration or injection or for surface anesthesia, for example, for application to the eye.

The new anesthetics are amines, that is, bases,

and will ordinarily be used in the form of salts,

for example, as a hydrochloride, sulfate, sulfamate, tartrate, glycolate or other salt, as the free bases themselves are quite insoluble in water. The'salt should have sufiicient solubility in water to be completely soluble in the concentrations used, which are usually of the order of 1% or less, should be capable of proper crystallization, etc. The hydrochlorides and the glycolates are among the salts particularly useful for therapeutic purposes.

The new compounds of the invention are the esters of p-amino benzoic acid with alkylamino butanols in which the alkyl group is a secondary group and has from 5 to 9 carbon atoms. These new compounds may be represented by the type formula NHZ C 0 0121mm in which R represents a secondary alkyl group having from 5 to 9 carbon atoms and R1 represents a butylene group.

It will be noted that these compounds are secondary airlines, that is, the amino group which is attached to the secondary alkyl group and the alkylene group is a secondary amino group, two of the hydrogens of ammonia having been replaced. To avoid confusion in terminology in the expression secondary alkyl amino as used in this specification and the appended claims, the term secondary will modify the term alkyl only, with the understanding that in every case the, amino group is secondary.

The new compounds are prepared by reacting p-nitro benzoyl chloride or other halide or p-nitro benzoic anhydride with a salt of the alkyl amino alcohol, and reducing the resulting nitrobenzoyl ester, catalytically or otherwise. An advantageous process involves condensing the p-nitro benzoyl compound with salts of secondary alkyl amino alcohols. The alkyl amino alcohols used as salts for the production of the p-nitro benzoyl esters are advantageously prepared by condensing the corresponding ketone with the corresponding amino alcohol and reducing.

Because of-theconvenience of purification and availability" of the intermediates, the compounds will ordinarily be prepared by condensing pnitrobenzoyl chloride with the hydrochloride of the alkylamino alcohol, and the ester produced in the form of the hydrochloride. If another pnitro benzoyl halide, for example, the bromide is used, or if the corresponding anhydride is used, other salts of the amino alcohol than the hydrochloride may be used.

The esters of alkyl amino alcohols which are tertiary alcohols are prepared advantageously by reaction of p-nitro benzoyl chloride or other halide or p-nitro benzoic anhydride with the amino alcohol to produce an amide, followed by rearrangement of the amide in the presence of an acid to a salt of the ester.

If the nitro ester is produced as the hydrochloride, it may be subjected in that form to reduction to produce the corresponding salt of the p-amino benzoic acid ester and the final product may be purified and used as the hydrochloride. On the other hand, if the p-nitro benzoate is produced 'as a salt with some other acid, it may be subjected to reduction in such form, or may be converted to the free base and reduced, in which case the final product will be the p-amino benzoate as the corresponding salt or the free base and may be purified and used as such. Further, if the p-amino benzoate is produced in the form of a salt with any given acid, it is readily converted to the salt of some other acid, by treatment with alkali to liberate the free base and subsequent neutralization-with the desired acid. If the free base is prepared, it may,

of course, be converted to the salt with any desired acid by simple neutralization. The conversion of the salt of the p-amino benzoate with one acid to the salt with another acid, or to the free base, or the neutralization of the free base to form salts, involve procedures which are well known to those skilled in the art and require no detailed description herein.

The invention will be further illustrated by the following specific examples, but it is not limited thereto.

Example I.-The preparation of the p-amino benzoic acid ester of 2-[4-(2,6-dimethylhepty1)- amino] -1-butanol.

10.8 parts of 2-[4-(2,6-dimethy1heptyl) -ami nol l-butanol (prepared, for example, as described in application Serial No. 344,163), now abandoned, are dissolved in 15 parts of clhoroform and the solution is saturated with dry hydrogen chloride gas. 9.4 parts of p-nitro ben- "chloride is filtered and purified by recrystallization from absolute alcohol: M. P. 154-156 C. 6 parts of the p-nitrobenzoate hydrochloride are suspended in 600 parts of distilled water and hydrogenated in the presence of one part of palladinized charcoal catalyst at room temperature. When reduction is complete,the catalyst is removed by filtration in an atmosphere of carbon dioxide and the filtrate concentrated to dryness in a vacuum. The p-amino benzoate hydrochloride is obtained as a pure White crystalline salt melting at 192-194" C. (dec.). If, instead of the hydrochloride, the free base is desired, it is readily prepared by dissolving or suspending the hydrochloride in a small volume, of alcohol, di-

luting with water and treating with an excess of sodium carbonate. The free base which is liberated is extracted with benzene. If a salt: with an-acid other than hydrochloric acid is desired, it is simply necessary to add to the solution of the free base, e. at, in benzene, the stoichiometric quantity of any suitable acid, evaporation of the solvent and crystallization giving the pure salt. In the foregoing example the reduction to form the amine compound is described as carried out by catalytic reduction in water using palladium supported on charcoal as the catalyst. duction may be carried out with the use of other liquids, for example, mixtures of water and alcohol, acetic acid and water or other liquids. Other catalysts than palladium, such as platinum, copper chromite, nickel, or the like, may be used with appropriate adjustment of the hydrogen pressure and temperature. If the nitro compound is reduced as a salt which through its acidic reaction would. attack the base metal catalysts such as nickel or copper chromite, noble metal catalysts are used. Chemical reduction may, of course, be

used. 1

Example I I .-Preparation ofthe p-aminobenzoio acid ester of 1isopropylamino-12-methyl-2- propanol. 27.8 parts of p-nitrobenz'oyl chloride in;140 parts of methylene chloride are added rapidly to a vigorously stirred mixture of 13.1 parts of l-isopropylamino-2-methyl-2-propanol in 200 parts of 5% aqueous sodium hydroxide. The mixture is heated to a temperature sufficiently high to cause refluxing of the methylene chloride for one hour, with vigorous mechanical stirring. The layers are separated and the aqueous layer is extracted once with methylene chloride. The combined. methylene chloride solutions are washed twice with water and concentrated to dry ness in a vacuum. The residue is recrystallized once from absolute alcohol, yielding the N-p-nitrobenzoyl derivative of 1-isopropylamino-2- methVl-Z-propanol, M. P. IDS-106 C.

11.2 parts of the above amide are dissolved in 40 parts of 95% alcohol. An excess (50% molar excess is satisfactory) of concentrated aqueous hydrochloric acid is added, and the solution is boiled for five minutes. The solution is cooled and distilled to dryness in vacuum. The residue This re- .carbon atoms and is dried by adding benzene and again distilling to dryness in vacuum, and is recrystallized from a mixture of methyl ethyl ketone and absolute alcohol. The p-nitrobenzoate hydrochloride of 1-isopropylamino-Z-methyl-2-propanol, M; P. 168-170 C., is hydrogenated by the method describedin Example I. Thep-aminobenzoate hydrochloride of 1isopropylamino-2-methyl-2-propanol, M. P. 1'75-176 C. (dec.) is obtained by recrystallization from methyl ethyl ketone.

Among the p-amino benzoic acid esters of secondary alkylamino butanols which are included in the invention and have valuable properties for local anesthetic uses are the esters of the following 2 [4- (2,6-dimethy1heptyl) amino] l-butancl l-isoprop-ylamino-2-methyl-2-propanol 2-isopropylamino- 1 -butanol 2- (B-pentylamino) -1-butanol 2- l-heptylamino) l-butanol 2-"sec. butylamino-2-methyl-l-propanol 2 (2-heptylamino) -2-methyl-1"-propan'ol I l- S-pentyl-amino) -2-methyl-2-propanol" 1- (2-heptylamino) -2-'methyl-2-propanol l-(2- oct ylamino) 2- nethyi-2 propanol Y) andothers' I g Of particular. importance are the}, amino benzoic acid esters of the 2-sec. alkyla inc-1;;

butanols and the l-sec. a1kylamino-2-methyl;2

propanolaas these series of compoundshave outstanding advantages for local anesthetic uses. In general, the compounds. which arederived from sec. alkylamino alcohols in whichthe-sec. alkylamino group and the hydroxylgrcpp are linked to contiguous carbon atoms are-superior to the compoundsin which these two grcupsare 2. As new therapeutic agents p-arnino acid esters of secondary alkylamino butanols in which the secondary alkyl group has from 5 to 9 in which the secondary alkylamino group and the ester group (0.00) are linked to contiguous carbon atoms. v, l H

3. The p-aminobenzoate of 2-[4-(2,6 dimethylheptyl)-aminol-1-butanol. V 4. The p-aminobenzoate'of 1- (2 heptylamino) Z-methyl Z-propanol. V ARTHUR 0. CORE.

REFERENCES CITED j The following references are of record in; P 

